Our studies demonstrate that the functions of various organs are markedly depressed in males, but not in proestrus females (with high estrogen [E2] levels) after trauma-hemorrhage and resuscitation (T-H). Moreover, estrogen receptor (ER) but not androgen receptor (AR) expression in cardiomyocytes from males was significantly decreased after T-H. Administration of E2 after T-H in males normalized cardiomyocyte ER and cardiac functions. Furthermore, administration of AR antagonist flutamide in males after T-H normalized cardiac E2 levels, ER levels, mitochondrial ATP levels, and cardiac functions. We hypothesize that the prevailing hormonal milieu in proestrus females helps maintain ER expression in cells of organs and thus preserves organ blood flow, prevents regional hypoxia, maintains mitochondrial ATP production and organ functions. The proposed studies will determine: a) the extent to which ER expression is decreased in cells and mitochondria of various organs in males and females in different stages of the estrus cycle and if the decreased ER is associated with altered mitochondrial ATP levels/organ functions; b) if E2 normalizes ER expression in all cells/organs, and restores organ functions after T-H; c) if cell-based therapy, i.e., administration of genetically modified bone marrow mesenchymal stem cells (MSC) to over-express ER will upregulate ERs in cells and improve organ function after T-H even in the absence of exogenous E2. Since regional hypoxia occurs after T-H in males, it is expected to produce endoplasmic reticulum (EPR) stress. We expect an inverse relationship between EPR stress and ER levels and E2 administration should alleviate EPR stress and normalize ER levels after T-H. Studies will also determine alterations in pro- and anti-apoptotic factors in various cells, mitochondrial ATP and free radical production following T-H in males and females, and whether E2 treatment normalizes these parameters and restores cell/organ functions after T-H. Since MSC therapy after T-H is expected to accelerate recovery of organs, we will determine if the combination of E2 and MSC therapy is more effective in improving cell/organ function and reducing mortality from subsequent sepsis. The integration of cell and organ functions using E2, cell-based therapy and other state-of-the-art cellular/molecular techniques, should identify novel mechanism(s) by which ERs regulate organ effector responses after T-H. The findings should facilitate the development and application of gender-specific therapy for preventing cardiovascular and other organ dysfunction and thus reducing morbidity and mortality from subsequent sepsis in male and female trauma victims. PUBLIC HEALTH RELEVANCE: We will examine the mechanisms by which the use of female sex hormones after trauma will improve cell and organ functions and decrease the lethality from infectious complications. We will use state-of-the-art molecular techniques and cell-based therapy to delineate the mechanisms involved in injury pathogenesis. The funding will help to develop gender-specific therapy. Such therapy should prevent organ dysfunction after injury and reduce morbidity and mortality from subsequent sepsis in male and female trauma victims.